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Nexavar (Sorafenib) Fails in Overall Trial but Looks Favorab


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Nexavar (Sorafenib) Fails in Overall Trial but Looks Favorable for EGFR Mutation-Positive Patients

http://blog.lungevity.org/2012/10/19/so ... fr-subset/

October 19th, 2012 - by Dr. Jack West

Nexavar (sorafenib), an anti-angiogenic pill-based “multi-kinase inhibitor” targeted therapy that is FDA approved in some other cancers such as renal cell and liver cancer, hasn’t been the subject of much discussion in lung cancer over the past few years. Early research done years ago in metastatic lung cancer showed that this agent has at least some activity in NSCLC, but it showed no benefit in the subsequent ESCAPE trial of Nexavar in combination with first line chemo. It did show encouraging results in KRAS mutation-positive advanced NSCLC (though this work wasn’t validated by more recent work that showed no benefit in this population), and also showed activity as a single agent for at least some patients with previously treated advanced NSCLC. But the results of a larger randomized MISSION trial of Nexavar with supportive care vs. placebo with supportive care as third or fourth line treatment for advanced NSCLC, presented at the annual conference of the European Society for Medical Oncology (ESMO) in Vienna, revealed no benefit for overall survival. There was, however, an apparent benefit in the subset of patients with an EGFR mutation who received Nexavar.

In the MISSION trial, 703 previously treated patients with advanced NSCLC were randomized to receive either Nexavar at the standard dose of Nexavar at 400 mg by mouth twice daily or placebo on the same schedule, along with supportive care for all patients. Those receiving Nexavar demonstrated a significantly higher response rate (P < 0.001) and a superior disease control rate (significant tumor shrinkage or stable disease) (P < 0.001) and progression-free survival ( (P < 0.0001), but they didn’t have any improvement in the primary endpoint of overall survival.

In addition to the full analysis of all of the patients on the trial, half of the patients enrolled on the MISSION trial had EGFR and KRAS mutation data available from tumor tissue or serum samples. Within that group, 26% of patients had an EGFR mutation, and 20% had a KRAS mutation. These mutations were balanced between the two arms of the trial.

Despite some of the prior work suggesting that Nexavar may be effective for KRAS mutation-positive NSCLC, there were no differences in outcomes with Nexavar in that group. However, the 89 patients with an EGFR mutation on Nexavar did show an approximately four-fold higher probability of not progressing at a given time point (HR 0.27; P <0.001) and an approximately two-fold higher probability of remaining alive at a given time point (HR 0.48; P = 0.002). For the EGFR mutation-positive subset, the median overall survival was than doubled in the Nexavar arm (423 days vs. 197 days).

While these results for the EGFR mutation-positive subset look very encouraging, the relatively small numbers and fact that this was an unplanned subset analysis means that this won’t lead to Nexavar being approved as a later line of therapy for this population. Any regulatory agency or insurer would say that this question requires a full-fledged prospective trial just for the EGFR mutation-positive subgroup. Unfortunately, even if that trial is developed, it will be many years before any results become available. But for now, with Nexavar being commercially available already, I suspect I won’t be the only oncologist interested in trying to obtain it for my EGFR mutation-positive patients. Whether it will be covered, or whether patients would want to pay for it if it isn’t covered, is a very open question.

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